Preparation of aryllithium compounds by metalation



United States Patent 3,534,113 PREPARATION OF ARYLLITHIUM COMPOUNDS BYMETALATION Jerome F. Eastham, Knoxville, Tenn., and Constantinos G.Screttas, Gastonia, N.C., assignors to Lithium Corporation of America,New York, N.Y., a corporation of Delaware No Drawing. Filed Feb. 8,1968, Ser. No. 707,020

Int. Cl. C07f 1/02; C07d 29/00, 27/00 U.S. Cl. 260-665 12 ClaimsABSTRACT OF THE DISCLOSURE Process of metalating aromatic hydrocarboncompounds, such as benzene or toluene, comprising reacting the aromatichydrocarbon with an organolithium compound, such as n-butyllithium, inthe presence of an ether, such as tetrahydrofuran, the ratio of thelithium in said organolithium compound to the ether being 1 gram atom ofthe lithium to from 0.25 to 4 gram moles of the ether.

Our invention relates to improvements in the preparation of aryllithiumcompounds.

The lithium metalation of aromatic hydrocarbons has heretofore beenproposed. Thus, for instance, benzene, toluene, and naphthalene havebeen metalated with n-butyllithium in various tertiary amines, indiethyl ether, in tetrahydrofuran (THF) and in mixtures thereof assolvents, but the yields have been unsatisfactory.

Our invention is predicated on the discovery that, through certaincontrolled use of the foregoing and other ethers in the manner hereafterdescribed, benzene can be metalated to phenyllithium, toluene tobenzyllithium, naphthalene to naphthyllithium, and other aromatichydrocarbons to other aromatic organolithium compounds in good yieldsranging from 70100% based on butyllithium and other organolithiums usedfor these metalations.

The ethers which catalyze these metalations are represented by linearalkyl ethers such as dimethyl ether, diethyl ether, diisopropyl ether,di-n-butyl ether and diisobutyl ether; dialkyl ethers of aliphaticpolyhydric alcohols such as dimethyl ether of ethylene glycol, diethylether of ethylene glycol, diisopropyl ether of ethylene glycol anddiisopropyl ether of diethylene glycol, and dimethyl-, diethylanddiisopropyl ethers of propylene glycol; cyclic alkyl ethers such astetrahydrofuran (THF), tetrahydropyran -(THP), dioxane, and 7-oxa[2,2,11-bicycloheptane (OBH); and liquid ethers in the form ofazaoxa-alkanes, aza-alkyloxacycloalkanes or oxa-alkylazacycloalkaneswhich can be represented by the formulae ice ( V) N-R or other divalentaliphatic hydrocarbon or alkylene radicals, preferably containing from 2to 4 carbon atoms; and n is 1 to 4. Illustrative examples of such ethersinclude, for instance, 2-dimethylaminoethylmethyl ether (CH NCH CH OCH 2diethylaminoethether and 2-dimethylaminopropylmethyl ether (CH N--CH CH-CH CH OCH An illustrative dioxacycloalkane is Lilo) For achievement ofthe results obtained pursuant to our present invention, the proportionsof the ethers to be added to the organolithium compounds employed inthese metalations fall within the range of 0.25 to 4 gram moles of etherper gram atom of lithium contained in the organolithium compound. Itappears that coordination complexes are formed by the interaction of theethers with the alkyllithium compounds employed. Thus, for example,after mixing the ether 7-oxabicyclo [2,2,1] heptane (OBH) with ahydrocarbon solution of n-butyllithium (BuLi), a solid complex,OBHzBuLi, can be crystallized from the solution.

The ethers are generally cleaved by organolithium compounds, thusconsuming them and decreasing the yields obtained in the metalationprocess. This loss of ethers to the cleavage reaction can besubstantially avoided by keeping the reaction temperature low,controlling the ratio of ether to organolithium compound, using etherswhich are not easily cleaved, and using ethers which are particularlyeffective in activating the compound. Depending upon the particularorganolithium compounds utilized, particular control of temperature ofthe metalation reaction is important for best results. Thus, veryreactive organolithium compounds as, for instance, secondaryalkyllithiums and tertiary alkyllithiums, can be used to metalateunreactive aromatic hydrocarbons in good yield because the ether,necessary to catalyze the reaction, is not itself consumed if thetemperature chosen is sufficiently low. At higher temperatures, even atroom temperatures in some cases, the catalyst is consumed more rapidlythan is the aromatic hydrocarbon metalated.

In general, it is preferred to operate at temperatures not exceeding 30C. and, better still, at temperatures in the range of 20 C. to 25 C.

The organolithium compound employed as the metalating agent is mostdesirably an alkyllithium compound such as ethyllithium,n-propyllithium, isopropyllithium, n-butyllithium, isobutyllithium,sec-butyllithium, tertbutyllithium, n-amyllithium, isoamyllithium,n-octyllithium, isooctyllithium, and the like, particularly analkyllithium containing from 2 to 6 carbon atoms. However, it may alsobe cycloalkyllithium compound, such as cyclohexyllithium ormethylcyclohexyllithium; or it may be an aryllithium compound when thelatter, for instance, is employed as the metalating agent for theproduction of aralkyllithium compounds, and among such aryllithiumcompounds are, for example, phenyllithium, tolyllithium, andphenylethyllithium. Still other types of organolithiums areheterocyclics such as 2 pyridyllithium and 2-lithiothiophene; andunsaturated organolithiums such as vinyllithium, allyllithium,crotonyllithium and propenyllithium. Again, polylithio-organiccompounds, including dilithiodienes, exemplified by 1,4- dilithiobutane;1,5-dilithiopentane; dilithioisoprene; dilithiobutadiene and otherdilithio adducts of other conjugated polyene hydrocarbons. Of specalimportance are the butyllithiums, particularly secondary butyllithium.

Aromatic hydrocarbons which can be metalated in accordance with ourpresent invention include, by way of example, benzene, toluene, biphenyland polyphenyls and their derivatives, o-, mand p-xylenes, mesitylene,durene, and polymethylbenzenes and polymethylpolyphenyl compounds ingeneral; alkylbenzenes such as ethylbenzene and isopropylbenzene andalkyl and polyalkylpolyphenyls in general; naphthalene and methylandethyl-naphthalenes. Still other aromatic hydrocarbon derivatives whichcan be metalated by the process of our invention are trialkyl andtriarylsilyl benzenes, dialkylaminobenzenes, and alkyl phenyl ethers.For example, metalation of trimethylsilylbenzene leads to a 90% yield ofa mixture of trimethylsilylbenzoic acid on carbonation of which 75% isthe meta isomer. Analogously, metalation of dimethylaniline permits a70% yield of O-dimethylaminophenyldiphenylcarbinol on reaction withbenzophenone. Of particular importance are benzene, toluene,naphthalene, methylnaphthalenes, and biphenyl.

In carrying out the process of our invention, generally speaking, theorganolithium compound is dissolved in an inert organic solvent,particularly a saturated aliphatic hydrocarbon solvent, and added to asolution of the ether in (a) the aromatic hydrocarbon to be metalated orin (b) a mixture of the aromatic hydrocarbon to be metalated plusanother saturated aliphatic hydrocarbon diluent under an inert gas. Thereaction mixture is stirred and cooled, if necessary, until the reactionis complete. Derivatization of the metalated aromatic hydrocarbons isaccomplished by carbonation to the respective organic carboxylic acidsor by bromination to the respective organic bromides. Various inertorganic solvents can be utilized as, for instance, pentane, hexane,heptane, octane and isooctane, as well as mixtures thereof. In somecases, an excess of the aromatic hydrocarbon to be metalated can be usedas solvent.

The reaction temperatures utilized are subject to quite wide variationalthough, for the reasons pointed out above, namely, to avoid or reducecleavage of the ethers by the organolithium compound, it is distinctlydesirable in most cases to operate at relatively low temperatures.Generally speaking, reaction temperatures may range from 20 C. or evenlower to as high as 80 C. or even somewhat higher. The particularorganolithium compound utilized, the particular aromatic hydrocarbon tobe metalated, and the particular ether utilized will all influence theselection of the particular temperature or range of temperatures atwhich optimum yields of the desired aryllithium compounds are obtained.

The following examples are given, by way of illustratration, ofpracticing the process of our invention. It will be understood thatnumerous other examples will readily occur to those skilled in the artin the light of the novel guiding principles and teachings disclosedherein.

EXAMPLE 1 6.5 ml. of a 1.6 M solution of n-butyllithium and containing0.01 gram atoms of lithium in hexane was added with stirring to asolution of 1.44 g. (0.02 gram moles) tetrahydrofuran (THF) in 30 m1. ofbenzene. The solution was stirred for 48 hours at 27 C. The reactionmixture produced was carbonated by pouring it into a dry ice-etherslurry. After workup, the derived acid product was analyzed by- NMRspectroscopy and found to contain benzoic acid corresponding to a 73%yield of phenyllithium based on starting n-butyllithium.

EXAMPLE 2 0.01 gram moles of tert-butyllithium in n-pentane (1.5 M) andcontaining 0.01 gram atoms of lithium, and 0.02 gram moles of dimethylether were mixed with ml. of toluene and stirred for two hours at 10 to-15 C. After carbonation and workup, a 79% yield of phenylacetic acidwas obtained.

Other metalations which have been carried out and conditions of theprocess and results are set out below. The Ether: BuLi ratio isexpressed in gram moles of the ether to gram atoms of the lithiumcontained in the butyllithium.

BuLi and 8 M in toluene, with the remainder being the ether and hexanesolvent. In Examples 4 and 5, the reaction solution was about 0.25 M inBuLi. The phenylacetic acid yield was obtained by taking the metalationreaction mixture, after the indicated reaction time, and

pouring it onto solid carbon dioxide slurried in diethyl ether.

EXAMPLE 6 Metalation of benzene with t-butyllithium (t-BuLi) Added etherTHF Ether: BuLi ratio 1:1 Reaction time (hr.) 2 Reaction temp. C.) 15 1OBenzoic acid yield (percent) 79 In Example 6, the reaction solution wasabout 0.25 M in t-BuLi and 8 M in benzene. The benzoic acid yield wasobtained in the same way as described in Examples 3, 4 and 5 in regardto phenylacetic acid.

The folllowing example is illustrative of the preparation of preformedcomplexes, of the charatcer described above, and, here again, in thelight of the novel guiding principles and teaching disclosed herein, thepreparation of numerous other complexes will readily suggest themselvesto those skilled in the art.

EXAMPLE 7 To a centrifuge tube containing 5 ml. of pentane was added 3.1ml. of n-butyllithium (0.005 gram atoms of lithium) from a 1.6 Msolution in hexane and 0.4 ml. (0.004 gram moles of 7-oxabicyclo [2,2,1]heptane (OBI-I). No precipitate was formed at room temperature. Oncooling to 5 0, crystals were formed which redissolved upon warmingabove 0 C. The crystalline precipitate was spun down at low temperatureand the supernatant was withdrawn. The precipitate was washed with two 5ml. portions of cold pentane and recrystallized from 5 ml. of pentane,all in the centrifuge tube. Finally the precipitate was dissolved in 0.4ml. of anhydrous benzene and this solution was analyzed by NMRspectrometry. The integrated signals of the methine protons of the etherand the protons of the methylene group adjacent to lithium indicated aratio of n-butyllithium to OBH equal to one.

EXAMPLE '8 To a reaction flask containing 400 m1. of a 2.52 N (1 gramatom of lithium) solution of sec-butyllithium in benzene 160 ml. oftetrahydrofuran was added dropwise to the stirred solution at 20 C. toC. during a period of 50 minutes. The reaction flask was then immersedin an insulated container with crushed Dry Ice so that the temperatureof the stirred solution was kept at -l0- -5 C. for 36 hours. At the endof this period the lightly yellow solution was 1.87 N in total base and1.82 N in active base. The yield of phenyllithium was 97%. An -aliquotof said solution was treated with an excess of trichloromethylsilane andthe mixture was analyzed by VPC. The yield based on the VPC-peak of thephenyltrimethylsilane was 100%.

EXAMPLE -9 To a solution of 0.2 mole of sec-butyllithium in 180 ml. oftoluene, there was added slowly 40 ml. of tetrahydrofuran at 15i1 C.When about of the tetrahy drofuran had been added, the temperature roserapidly to 0 C. and the entire mixture froze into a yellow crystallinemass. The remainder of the tetrahydrofuran was added at once and thesolution was allowed to attain room temperature at which time most ofthe solid went into solution. Addition of 10 ml. of tetrahydrofuransolubilized the entire precipitate. Oxidimetric titration indicated anormality of 0.76 (theoretical 0.80). The yield of benzyllithium was95%.

EXAMPLE 10 To a 250 ml. three-necked flask equipped with refluxcondenser, magnetic stirrer and thermometer, previously purged withnitrogen, was added 50 ml. of benzene followed by 2 ml. of ca 90%n-butyllithium. Titration with sec-BuOH 9,10-phenanthroline of a 5 ml.aliquot of this solution indicated a normality of 0.47. Two ml. of 2-dimethylamino methyltetrahydrofuran was added. The mixture was thenheated to reflux during a period of 10 minutes. Reflux was continued for20 minutes longer and then the mixture was cooled rapidly to 25 C.Titration of a 5 ml. aliquot showed that the solution was 0.38 N inactive lithium. Carbonation of the entire reaction mixture, followed byworkup and recovery gave 1.52 g. of benzoic acid M.P. 115-117 C. Thus,the yield based on titration was 81% and 63% based on carbonation.

We claim:

1. A process for the preparation of aryllithium compounds whichcomprises metalating an aromatic hydrocarbon with an organolithiumcompound in the presence of an ether, the ratio of the lithium in saidorganolithium compound to the ether being 1 gram atom of lithium to from0.25 to 4 gram moles of the ether.

2. A process according to claim 1, wherein the ratio of the lithium insaid organolithium compound to the ether is 1 gram atom of lithium tofrom 1 to 2 gram moles of the ether.

3. A process according to claim 1, wherein the temperature at which themetalation is conducted is not above 30 C.

4. A process according to claim 2, wherein the organolithium compound inthe form of a solution in an inert organic solvent is added to asolution of the ether in the aromatic hydrocarbon to be metalated.

5. A process according to claim 3, wherein the organolithium compound isan alkyllithium.

6. A process according to claim 3, wherein the ether is a linear alkylether or a cyclic alkyl ether.

7. A process according to claim 3, wherein the ether is 7-oxabicyclo[2,2,1] heptane.

8. A process according to claim 4, wherein the inert organic solvent isat least one selected from the group pentane, hexane and heptane.

9. A process according to claim 5, wherein the ether is a linear alkylether or a cyclic alkyl ether.

10. A process according to claim 9, wherein the alkyllithium issec-butyllithium and the aromatic hydrocarbon to be metalated is benzeneor toluene.

11. A process according to claim 1, wherein the reaction is carried outin an inert liquid hydrocarbon medium.

12. A process according to claim 5, wherein the alkyllithium containsfrom 2 to 6 carbon atoms.

References Cited UNITED STATES PATENTS 3,197,516 7/1965 Esmay 260-665OTHER REFERENCES Eastham, et al.: J. Am. Chem. Soc. (1963), pp. 2171-2.

Talalaeva et al.: Chem. Abst. 51 (1957) (col. 1962).

Kirk: Othmer Encyclopedia of Chemical Technology, vol. 12 (1967),Interscience Publishers, New York, N.Y., pp. 550-1.

Gilman et al.: J. Org. Chem. 23 (1958), pp. 1476-9.

HELEN M. MCCARTHY, Primary Examiner A. P. DEMERS, Assistant Examiner US.Cl. X.R.

